CZ9902323A3 - Valve for aerosol container - Google Patents

Abstract

Valve for an aerosol container for dispensing a suspension of a substance in a liquid propellant contained therein. The valve comprises a valve body (1) having at least one orifice (16) to allow a quantity of the suspension to pass from the container into the valve. The valve further comprises a ring (18) disposed around the valve body (1), the ring being positioned below the at least one orifice to reduce the volume of suspension that can be accommodated within the container below the at least one orifice when the container is orientated with the valve at the bottom, the ring having at least one portion of reduced axial thickness to provide a trough (19) around the valve body below the at least one orifice. <IMAGE>

Description

Technical field

The present invention relates to a valve for an aerosol container by means of which a certain amount of the contents of the container can be dispensed. The invention has particular utility for delivering metered doses of medicaments, although it is useful for dispensing aerosols in general.

BACKGROUND OF THE INVENTION

When administering solids in aerosol form, it is common to use a so-called suspension aerosol. This includes the use of a liquid propellant in which a solid to be administered is suspended. Inevitably, there is a difference, but very small, between the respective specific weights of the propellant and the solid to be administered, which means that over time and in the absence of other superior interactions, the two components tend to separate in the container, wherein the lighter component pushes to the top or the heavier component passes to the bottom over time.

In some pharmaceutical aerosols, the drug particles are denser than the propellant and hence these particles tend to settle at the bottom of the container. This phenomenon can be reduced by additional structuring of the drug formulation that will improve its physical stability, for example by controlled flocculation. Controlled flocculation of the suspension may increase the effective particle size of the dispersion from less than 10 µm to more than 100 µm. Depending on the square of the particle radius iq directly increases the settling rate in such circumstances.

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Suspension aerosol users are always instructed to shake the container well before use. However, even a short interval between the end of shaking and the initiation of the aerosol dose is sufficient to allow some sedimentation to occur. This poses a problem where the suspended material is a drug because it may result in the patient receiving a dose that, although having the correct volume, contains either too little or too much drug.

This problem has been found to be particularly acute in the development of CFC-free aerosol formulations using 1,1,1,2-tetrafluoroethane, also known as HFA134a, which is less dense than conventional CFC propellants.

In some aerosol drug formulations utilizing this propellant, when the container is oriented with the valve at the bottom, drug particles quickly settle on and around the valve and find their way into the valve body during vibrations caused, for example, by transport. The entrapped drug is then not completely dispensed, even after shaking, due to the narrowing of the body

At the Q valve, and after the valve has been emptied and actuated, the trapped medicament enters the dosing chamber, resulting in a high drug content in the dose administered at the next actuation. This problem is particularly pronounced when the drug used is fluticasone propionate.

UK Patent No. 2195986 discloses an aerosol valve having a collection point, i.e., a point at which liquid passes from the interior of the container to the valve collection chamber, at a point spaced apart by a noticeable vertical distance from the nearest vertical valve orientation a substantially horizontal surface. Although this valve •

ensures that the liquid entering the dosing chamber following the administration operation comes from the space above the nearest area where settled particles could collect, any settling particles that could be drawn into the collection chamber, together with any drug particles that sediment from the suspension within this collection chamber, tend to be retained and are not administered after shaking. In addition, by deliberately placing the collection point substantially higher than the lowest point of the container, a significant amount of the contents of the container cannot be dispensed at all, resulting in considerable waste.

It is an object of the present invention to provide a valve that reduces the above-mentioned problems.

SUMMARY OF THE INVENTION

According to the present invention, a valve is provided for an aerosol container for dispensing a suspension of a substance in a liquid propellant contained in a container, the valve comprising a valve body having at least one orifice to allow a certain amount of suspension to pass from the container to the valve. said valve further comprising a ring disposed around said valve body, said ring being located below said at least one orifice to limit the volume of suspension that may be contained within said container below said at least one orifice when the container is oriented with the valve at the bottom, and wherein the ring has at least one portion of limited axial thickness to secure grooves around the valve body below said at least one orifice.

By forming a ring under at least one orifice to limit the volume of suspension that may be contained

inside the container below the mouth (s), when the container is oriented with the valve at the bottom, it is ensured that most of the contents of the container can be dispensed, thereby reducing waste, while a groove around the valve body below the mouth (s) secured by at least one part with reduced axial the thickness serves to contain any sediment of drug particles, thereby ensuring that the suspension entering the collection chamber comes from a space above an area in which any deposited drug particles could collect.

Preferably, the valve is a metering valve comprising a metering chamber, a collection chamber, a transfer passage through which a certain amount of suspension may pass from the collection chamber to the metering chamber, and a valve stem having a dispensing passage through which a dose of suspension can be dispensed from the metering chamber. in the first position, the dispensing passage is separated from the dispensing chamber and the dispensing chamber is connected to the collecting chamber through the transfer passage, and in the second position the dispensing passage is connected to the dispensing chamber and the θ transfer passage is separated from the dispensing chamber. a metering chamber dispensing chamber having a plurality of orifices to allow a certain amount of suspension to pass from the container to the collection chamber.

By providing a valve body having a plurality of orifices to allow the slurry to pass from the container to the collecting chamber, the slurry can flow freely through the collecting chamber, thereby allowing the slurry contained within the collecting chamber and inside the container to agitate when the container is shaken. collecting chambers scatter.

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Preferably, the orifices of the slots extend in the axial direction. Preferably, the slots extend substantially along the entire axial length of the collecting chamber.

By providing slits along the length of the collecting chamber 5, the suspension can flow freely through the entire collecting chamber, thereby allowing maximum dispersion of drug particle deposits within the collecting chamber.

Preferably, more than two slots are formed.

Preferably, the ring further comprises a seat for placing a gasket between the container and a valve for sealing the container.

By providing a seat on the gasket seating ring, the gasket is smaller in size and the area of the gasket that is exposed to the contents of the container is also reduced.

Preferably, the ring further comprises a plurality of slats separated by slits on its periphery and extending substantially upwardly when the container is oriented with the ²⁰ valve at the bottom.

By forming the slats separated by slits at the periphery of the ring, the slurry is forced to flow around the slats and through the slots as the container is shaken, the resulting swirling movement of the slurry helping to disperse 25 of any drug particle deposits on and around the ring.

Preferably, the substance to be dispersed is a drug suspended in liquefied HFA134a. Preferably, the drug is fluticasone propionate.

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The present invention will be described in more detail below by way of example embodiments with reference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS 5

Fig. 1 is a cross-sectional view through a dispensing valve according to a first embodiment of the present invention;

Giant. 2 is a cross-sectional view through the dispensing valve 10 according to the first embodiment of the present invention;

Giant. 3 is a partial cross-sectional perspective view of a ring for use with the valve of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The valve according to the first embodiment of the present invention, as shown in Fig. 1, comprises a valve body 1 sealed in the ferrule 2 by means of

The ferrule 2 is itself fitted onto the neck of the container (not shown) with the insert of the gasket 3, as is well known in the art. The container is filled with a suspension of drug in HFA134a liquid propellant. Medicaments suitable for this purpose are, for example, for the treatment of respiratory diseases such as asthma, bronchitis, chronic lung obstruction diseases and bronchial infections. The additional drugs may be selected from any other suitable drug useful in inhalation therapy, which at the same time may be presented as a suspension. Thus, suitable drugs may be selected, for example, from 30 analgesics, such as coded, dihydromorphine, ergotamine, fentanyl or morphine; angina preparations such as diltiazem; anti-allergic agents such as cromoglycate, ketotifen or nedocromil; anti-infective agents such as cephalosporins, penicillins, streptomycin, sulfonamides, tetracyclines and pentamidine; antihistamines such as methapyrilene; anti-inflammatory agents such as fluticasone propionate, beclomethasone, dipropionate, flunisolide, budesonide or triamcinolone acetonide; an antitussive such as noscapine; bronchodilators such as salbutamol, salmeterol, ephedrine, adrenaline, phenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharin, tulobuterol, or (-) - or - - -. -dichloro-cis - [[[6- [2- (2-pyridinyl) ethoxy] hexyl] amino] methyl] benzenemethanol; diuretics such as amiloride; anticholinergents such as ipratropium, atropine or oxitropium; hormones such as cortisone, hydrocortisone or prednisolone; xanthines such as aminophylline, choline theophyllinate, lysine theophyllinate or theophylline, and therapeutic proteins and peptides such as insulin and glucagon. It should be understood by those skilled in the art that where appropriate, the drugs may be used in the form of salts (e.g., as alkali metal or amine salts or as acid salts) or as esters (e.g., low alkyl esters) or as solvates (e.g., hydrates) ) to optimize drug activity and / or stability. Preferred drugs are salbutamol, salbutamol sulfate, salmeterol, salmeterol xinafoate, fluticasone propionate, beclomethasone dipropionate, and terbutaline sulfate. It should be understood that the drug suspension may consist purely of one or more active ingredients.

The valve body 1 is formed in its lower part with the dosing chamber A and in its upper part with the collection chamber 5

The upper and lower terms are used for the container when in orientation when used with the container neck and the valve at the lower end of the container that corresponds to the valve orientation as shown in Figure 1. A valve stem 7 is disposed in the valve body and the valve body 8 extends out of the valve through the stem stem seal 9 and the ferrule 2. Part 8.

the shaft is internally formed with an inner axial or longitudinal channel 10 open at the outer end of the shaft 10 and connected to the radial passage 11.

The upper portion of the valve stem 7 has a diameter such that it can slide slidingly through the opening in the stem stem seal 12 and will engage the periphery of the opening sufficiently to provide a seal. The upper stem seal 12 is held in position against the step 13 formed in the valve body 1 between the lower and upper portions by a sleeve 14 that defines a metering chamber 4 between the lower stem seal 9 and the upper stem seal 12. The valve stem 7 has a passage 15 which, when the stem 7 is in its inactive position shown, provides a connection between the metering chamber 4 and the collecting chamber 5, which itself is connected to the interior of the container via a mouth 16 formed in the side of the valve body 1. . These orifices 16 include three slots arranged at equal angular spacing about the valve body 1 and extending in the axial direction therethrough, each slot having a width of approximately 1 mm and a length of 30 slightly less than the length of the collecting chamber 5, so that the slurry

Inside the container it can flow freely through the entire collection chamber 5. ·

The valve stem 1 is biased downwardly into the inactive position by means of a return spring 6 and is provided with a collar 17 that abuts against the lower stem seal 9. In this inactive position, as shown in FIG. 1, the collar 17 rests against the lower shaft seal 9 and the radial passage 11 is open below the lower shaft seal 9 so that the dosing chamber 4 is separated from the channel 10 and the suspension inside cannot escape.

The ring 18 is disposed around the valve body X under the slots, and is formed with a plurality of reduced axial thickness portions providing a U-shaped cross section that extend in a radial direction to form a plurality of grooves 19 around the valve body 1. As shown in FIG. As seen in Figures 1 and 3, the ring 18 is formed as a separate component made of nylon or other suitable material, and has an inner annular contact edge with a diameter suitable to provide a frictional fit over the top of the body and valve, the ring 18 is seated opposite the step 13 below the mouths 16 formed by slits. However, the ring 18 may alternatively be manufactured as an integrally molded body and valve portion.

The outer wall of the ring 18 extends in the axial direction and is formed with a plurality of angularly equally spaced slots to form lamellae 20 that extend upwardly from the bottom of the ring 18, as best seen in Figure 3. As shown in FIG. 3, six slots and six slats 20 are formed, although not all are shown in this view in partial cross-section. However, it should be understood that more or less could be used

slots and slats. The bottom of the ring 18 is further provided with a seat 21 for the gasket 3, which helps to position the gasket 3 in the correct position during assembly and also allows the inner diameter of the gasket 3 to be increased, thereby reducing the weight of the gasket 3. and a gasket area 3 exposed to material within the container. This can offer a significant advantage where there are problems with the dirt that leaches from the gasket 2 into the material contained in the container.

To use the device, the container is shaken to homogenize the suspension within the container. As the container is shaken, the suspension in the container flows freely through the slots forming the orifice 16 in the collection chamber 5 to ensure that the suspension in this collection chamber 5 is continuously mixed with the suspension in the container. This not only ensures the homogeneity of the suspension within the container and the collection chamber 5, but this flow of suspension also serves to disperse any drug particle deposits that could precipitate from the suspension within the collection chamber 5. Shaking the container also causes the suspension to flow around the lamellae 20 and the resulting turbulence and vortex movement of the suspension aid in dispersing any drug particle deposits on and around the ring 18.

The user then pushes the valve stem 7 against the force of the return spring 6. When the valve stem 4 is compressed, both ends of the passage 15 come to a position in which they lie on the side of the stem upper gasket 12 spaced from the metering chamber 4. Thereby, a dose is metered within the dosing chamber 4. Continued compression of the valve stem 7 moves the radial passage 11 into the dispensing chamber 4 while the upper seal 12

the stem seal against the valve stem body 2. Thus, the metered dose can flow out through the radial passage 11 and the outlet channel 10.

Releasing the valve stem 2 causes it to return to the illustrated position under the action of the return spring 6. The passage 15 then once again provides a connection between the metering chamber 4 and the collection chamber 5. Accordingly, at this stage, the liquid passes under pressure from the container through the orifice 16. which form the slots and through the passage 15 and hence into the metering chamber 2 to fill it.

It can be seen that in the active orientation of the container and the valve, as shown, the arrangement of the U-shaped ring 18 around the valve body 2 provides a groove 19 which lies at a noticeable distance below the orifices 16 formed by the slots. This groove 19 serves to receive any deposits of drug particles that have not been re-dispersed into the suspension, and thus ensures that the suspension entering the collection chamber 5 through the orifice 16 is drawn from the region containing a homogeneous suspension that has no drug deposits. of particles.

In addition, the ring 18 serves to limit the volume of the suspension that can be received inside the container below the slits 16 formed by the slits. This ensures that most of the contents of the container can be dispensed, with the only amount of suspension to be discarded corresponding to the limited volume remaining below the slots after the level of the suspension has fallen below the level from which it can enter the collection chamber.

Table 1 and Table 2 present the end of milligram dispensing lifetime when administered from two sets of five ftft ft ftft ftft inhalers each. Both tables show data derived from inhalers containing equivalent for 160 doses of a suspension of fluticasone propionate in liquid HFA134a with a target dose of 120 doses plus 40 extra doses to allow for losses and leakage. Data from start-up # 115 is shown because the data for both sets of inhalers are consistent up to this point. Table 1 shows data from the first set of five conventional inhalers having a ring-free valve. Table 2 shows data from a second set of five inhalers having ring valves according to the present invention:

Table 1:

End of dosing life for valve without ring

Batch no.

115

116

117

118

11!

120

121

122

123

124

Batch weight

Inhaler

Inhaler

Inhaler (mg)

Inhaler

Inhaler

Batch no. Inhaler 1 Batch weight (mg) Inhaler 2 Inhaler 3 Inhaler 4 Inhaler 5 125 62 42 47 47 59 126 62 59 64 63 60 127 49 61 53 42 37 128 61 61 63 61 62 129 63 57 39 63 63 130 63 62 63 63 62 131 60 41 34 38 45 132 62 61 61 60 59 133 44 43 39 49 61 134 60 62 58 62 60 135 32 60 17 26 44 136 58 61 60 59 61 137 49 54 58 51 59 138 48 45 34 59 59 139 25 16 14 29 16 140 37 18 20 May 5 12 141 6 8 5 7 18 142 47 23 30 27 Mar: 38 143 10 29 23 15 Dec 22nd 144 9 16 18 31 36 145 30 37 29 33 48 146 42 41 32 30 46

Table 2:

End of dosing life for ring valve

Batch weight (mg) Inhaler Inhaler Inhaler Inhaler Inhaler Batch no. 1 2 3 4 5 115 60 61 61 60 62 116 62 61 61 61 63 117 61 60 60 60 61 118 61 61 61 60 62 119 60 59 60 60 61 120 60 61 60 60 62 121 60 59 60 59 62 122 60 60 59 59 60 123 61 61 61 61 61 124 61 60 61 61 63 125 61 60 60 59 31 126 61 60 61 60 62 127 61 59 61 60 61 128 61 61 61 60 63 129 62 58 61 61 57 130 62 61 61 61 63 131 60 61 61 60 60 132 61 60 61 61 62 133 61 61 61 60 62 134 61 61 61 61 62

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Batch no. Inhaler 1 Batch weight (mg) Inhaler 2 Inhaler 3 Inhaler 4 Inhaler 5 135 61 60 60 60 62 136 61 60 60 60 62 137 59 60 59 58 60 138 59 59 59 59 60 139 59 55 59 60 55 140 31 61 61 59 60 141 25 48 61 60 33 142 61 60 61 60 60 143 21 9 23 20 May 26 144 17 ²⁵ 32 26 25 145 44 32 36 25 35 146 17 9 26 19 Dec 28

It can be seen from Table 1 that the batch weight begins to become considerably inconsistent after the run number 124 for the ring-free valves, whereas from Table 2 it can be seen that the batch weight remains relatively consistent up to the run number 137 and then quickly disappears for these. valves according to the present invention which comprise a ring. Thus, it is apparent that the ring has a significant effect on the end of the dosing life.

ti ti ti ti ti ti ti ti ti ti ti ti ti ti *

«Ti • ti ti ti •

ti ti

-Ί ti-ti-ti-ti-ti-f-ti-ti-ti-ti-ti

The valve according to the second embodiment of the present invention, as shown in Figure 2, is a variant of the valve shown in Figure 1, in which the corresponding elements have been designated with the same reference numerals as used in Figure 1. The main difference between the two embodiments is that The valve according to FIG. 2 utilizes a different body and valve structure having a single orifice 26 allowing connection between the collection chamber 5 and the interior of the container. The valve of this alternative is operated in exactly the same manner as described in connection with the valve shown in Fig. 1. The valve of Fig. 2 could be used with suspensions where the settling problem within the collecting chamber is not as acute, but in which however, settling around the valve remains a problem.

Table 3 demonstrates improved dose reproducibility that is achieved using a valve according to the first embodiment of the present invention with a body having three slots as shown in Fig. 1, compared to a valve according to the second embodiment of the present invention with a body having only one orifice as shown in Fig. 2 when a fluticasone propionate suspension in liquefied HFA134a is used. The results shown in the table are average dose weights delivered from at least five inhalers. For each inhaler, doses from two actuations were measured before each inhaler was subjected to a vibration test to simulate the effects of transport, followed by measurements from two additional actuations:

Ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft Ftft

ftft

Table 3

Effect of vibration on the administered dose

Valve type Dose in pg { 1. Launch Before vibration Dose in pg 1. Launch after vibration 2. startup 2. startup Body s one mouth 233 246 217 688 Body three slits 288 285 275 317

The data presented in Table 3 clearly shows that the extreme dose variability characteristics verified for valves having a single collection point (orifice), due to the high tendency of fluticasone propionate to settle in liquefied HFA134a, are substantially limited to a three-slot body.

It should be understood that the present disclosure has been presented solely for the purpose of illustration, and the present invention may be subject to modifications, changes and improvements without departing from the scope thereof.

Claims (9)

PATENTOVÉ Claims ············· · 9 · · 99 99 9 9 9 9,999 • 9,9 9 99 99 9 9 9 9 9,999,999 9 9 99 99 A valve for an aerosol container for dispensing a substance suspension in a liquid propellant contained in a container, the valve comprising a valve body having at least 5 orifices to allow a certain amount of suspension to pass from the container to the valve, wherein the valve further comprises a ring disposed around the valve body, the ring being located below said at least one orifice to limit the volume of suspension that may be contained within the container below said at least one orifice when the container is oriented with the valve at the bottom, and wherein the ring has at least one portion with limited axial thickness to secure a groove around the valve body below said at least one orifice. The valve of claim 1, wherein the valve is a metering valve comprising a metering chamber, a collection chamber, a transfer passage through which a certain amount of suspension may pass from the collection chamber. And a valve stem having a dispensing passage through which a slurry dose can be dispensed from the dispensing chamber, the valve stem being slidably displaceable within the valve body such that in the first position the dispensing passage is separated from the dispensing chamber and the dispensing chamber. Yippee 25 connected to the collecting chamber through the transfer passage, and in the second position the dispensing passage is connected to the dispensing chamber and the transfer passage is separated from the dispensing chamber, the valve body having a plurality of orifices to allow some slurry to pass from the container into the collection chamber. 99 99 9 9 999 999 9 9 ·· ·· · · · ··· · · « 9 9 9 9 9 9 9 9 9 9 9 999 9 9 9 99 99 The valve of claim 2, wherein the orifices are slots extending in a substantially axial direction. 4. The valve of claim 3, wherein the slots extend substantially over the entire axial length of the collection chamber. Valve according to any preceding claim, characterized in that more than two slots are provided. The valve of any preceding claim, wherein the ring further comprises a seat for receiving a gasket for sealing the container. The valve of any preceding claim, wherein the ring further comprises a plurality of slats separated by slits on its periphery and extending substantially upwardly when the container is oriented with the valve at the bottom. An aerosol container comprising a valve according to any preceding claim for aspirating a suspension of medicament in liquefied HFA134a. An aerosol container according to claim 8, wherein the drug is fluticasone propionate.